Over 60% of patients with advanced cancer suffer from anorexia, or loss of appetite. Cancer patients describe it as their 3rd most noxious symptom, outranked only by pain and fatigue. Yet palliative options are limited. The two most commonly prescribed orexigens are progestational agents and corticosteroids. Independent of a placebo effect, however, only 20% of cancer patients describe appetite improvement with their use. Neuropeptide y (NPY) offers a novel approach. Two pieces of evidence justify further study of this naturally occurring hormone in this setting. First, our group found that advanced cancer patients with severe anorexia (defined as < 50% of their premorbid intake, as measured by a validated questionnaire) manifest lower circulating concentrations of NPY compared to historical controls, a finding which raises the possibility that hormonal repletion may improve appetite. Second, even in non-tumor-bearing animals, NPY is "the most potent feeding stimulus known." Both direct NPY-receptor interactions within the brain's feeding centers and alterations in the body's hormonal milieu may account for these orexigenic effects. We propose 2 pilot studies to allow us to begin testing NPY for cancer-associated anorexia. First, we will test the hypothesis that a biologically active, relatively non-toxic dose of NPY can be administered. We propose a phase I trial with an estimated maximum of 36 advanced cancer patients to evaluate changes in cortisol, adrenocorticotropic hormone (ACTH), and leptin as well as toxicity and systemic exposure of intranasal NPY. Second, because NPY's orexigenic effect may be receptor-mediated, we will test the hypothesis that NPY Y1 and Y5 receptor polymorphisms are associated with anorexia in cancer patients independent of serum NPY. We propose a case control study (75 patients/group) to explore associations between these polymorphisms and anorexia and will incorporate these polymorphisms as stratification/adjustment factors in larger, future NPY trials should such associations be found. These two pilot studies will allow us to lay the groundwork for such larger trials. Our ultimate goal is to help cancer patients who suffer from anorexia.